Welcome to Rusk Insights on Rehabilitation Medicine, a top podcast featuring interviews with thought leaders in the field of PM&R from Rusk Rehabilitation at NYU Langone Medical Center and other prominent rehab medicine institutions. Your host for these interviews is Dr. Tom Elwood. He will take you behind the scenes to look at what is transpiring in the exciting world of rehabilitation research and clinical services through the eyes of those involved in making dynamic breakthroughs in health care. So listen, learn and enjoy. Hello and welcome to another episode of the Rusk Rehabilitation podcast series at NYU Langone Health. These interviews make it possible to learn about developments in the field of rehabilitation aimed at improving the lives of patients. Podcast listeners have an opportunity to listen to interviews with exceptionally knowledgeable and interesting participants. Each segment is in the 15 to 20 minute range apart from the introduction of speakers. Occasionally, a pair of longer recordings is featured by individuals who participated either in grand rounds presentations or in symposia at the Rusk Institute of Rehabilitation at NYU Langone Health. We are wanted to have us today's guest, Dr. Steven Dukoski, who is professor of Alzheimer's Research at the University of Florida College of Medicine and Deputy Director of the McKnight Brain Institute at that institution. In part one, Dr. Dukoski discussed the history of developments involving chronic traumatic encephalopathy. CTE is presentation addressed head injuries and sports such as football and boxing along with a growing increase in interest pertaining to brain disorders involving war related blast injuries from IEDs and the discovery that participation in other sports also can result in similar injuries. Today, we are hosting Dr. Steven Dukoski, who is the Earth's Cost for Professor of Alzheimer's Research at the University of Florida College of Medicine, the Deputy Director of the McKnight Brain Institute and Associate Director of the one Florida Alzheimer's Disease Research Center, the ADRC. He is also the professor of neurology and neuroscience at UF. And from 2008 to 2013, Dr. Dukoski was Vice President and Dean of the University of Virginia School of Medicine and Physician and Chief of the University of Virginia Health System. Prior to moving to UVA, he was chair of the Department of Neurology at the University of Pittsburgh, UPMC, and directed the pit ADRC for 14 years. His basic research centers on structural and neurochemical changes in human brain and aging and dementia and effects of traumatic brain injury. His clinical translational research is in understanding the cognitive and behavioral decline, genetics, neuroimaging, and treatment and prevention of AD. He offered with Bennett Amalu, the first reports of CTE in American football players, and was principal investigator of the program project grant, studying the clinical application of the breakthrough amyloid imaging agent Pittsburgh Compound B for PIB. Dr. Dukoski has served on and led numerous NIH review and advisory committees and served on two NIH councils, the National Advisory Council of the National Center for Complementary and Alternative Medicine, now the National Center for Complementary and Integrative Health, and the NIH's Council of Councils, the Director's Council, from 2013 to 2015. Dr. Dukoski was a member of the Board of Directors of the Alzheimer's Association for 16 years and chaired the Association's Medical and Scientific Advisory Council for five years. He's a former member of the Board of Directors of Alzheimer's Disease International, or ADI, who is now a member and former chair of the ADI Medical and Scientific Advisory Panel. In 2003, he was elected to the American Board of Physiatry and Neurology, ABPN. In 2010, he was elected president of the Neurology Council and vice president of the ABPN. Dr. Dukoski has received multiple national and international awards for his work in AD, including the Lifetime Achievement Award for the Alzheimer's Association International Conference. And without further ado, I will hand it over to Dr. Dukoski. Thank you so much again for being here. Good morning, everyone. It's very nice to talk to you this morning. I'm going to quickly share my screen so that we can get started. I'll try to leave some time at the end if there are any questions. So I'm going to talk about a bit of history because CTE has a fascinating history and there are still questions about it. Some of the questions are old, some of the questions are new, but they're all really interesting with respect to both injury to the brain and how you try to repair it. And we'll talk a bit about future directions because there's all show you the data keep coming fast and furious with respect to new information, especially because of non-invasive ways of assessing the brain. These are my disclosures. There is nothing about my presentation today that is involved in any of these, however, if you believe that there is, I would like to know it if you would just send me an email. It's my last name at ufl.edu. This is an overview of almost all of the different kinds of traumas that you can encounter. What happens immediately with a relatively severe trauma is diffuse axonal injury, which will give you all kinds of somewhat unpredictable ways of seeing abnormalities. Synaptic loss certainly ischemia with respect to swelling in the brain and neuronal dysfunction or demise depending on how severe the injury is. And surviving means disruption of circuitry, which will also be reflected in behavior and impaired axonal transport and circuit disruption, which may result not only in inadequate cognition, but also sometimes in altered or strange responses. So that's the trauma. The outcomes, this is the lower end blown up, is the area that we are concerned about today. Mild traumatic brain injury or mild TBI usually means at least being transiently and knocked unconscious or at least stunned in some way. There may or may not be mild to dema. It's not clear whether there is short term pathology that lasts a bit. And there may be in fact a contusion, but many times there is not. So the recovery in this case is usually good from a single variable neuropsychiatric or chronic cognitive complaints occur, and as many of you know, mild TBI is frequently associated with PTSD, common in some circumstances that we'll talk about in a bit. Then we have the discovery of the new, relatively new phenomenon of brain alterations with mild repetitive TBI. Here, we know there are axonal and cytoskeletal alterations, aggregates of abnormal protein, mainly tau protein, which in Alzheimer's disease and in repetitive TBI results in aggregation of abnormal tau, those are neurons filled with neurofibrillary tangles at the bottom. And it's associated with dementia pugilistica, chronic traumatic encephalopathy, and pugilistic Parkinsonism, which was actually a relatively commonly observed problem in the early days of boxing. If you have the variant of the apolipo protein E form called Epsilon4 or E4, you are more likely to develop Alzheimer's disease and you are also more likely to develop the pathology if you have mild repetitive TBI. Severe TBI, in many cases of which, of course, come to you are people who have chronically impaired homeostasis and homeostasis. They also have accumulation of brain aggregates, including both A-beta and tau pathology. And those are the pathologies of Alzheimer's disease. We are still not clear exactly how much of an increased risk of Alzheimer's disease there is with a single severe TBI, but we are learning more about the long-term effects of it. And I will talk about that briefly. And if you reestablish your homeostasis and you clear your protein aggregates, you may or may not have some residual cognitive or neuropsychiatric impairment, but you may well get back to function and that's what we call resilience or resistance to chronic disease. So CTE is a very curious disorder, only relatively recently defined clearly. This is a map from the National Library of Medicine on the number of publications about chronic traumatic encephalopathy by year, and what you see is that around the mid-2000s, mid-ox, as they say, the pathology first having been described way back in the past, but also again in 2005 with the first case of pathology of CTE and then up it went. I didn't get to put in 23 here, but I have no reason to think that they're not on a trail to also be increased above the prior. So boxing is where CTE came from initially, Plato who always says something good to say to us. So surely if we were boxers, we would have been learning to fight many days before and exercising ourselves and imitating all of those blows and wards which we were intending to use in the hour of conflict, meaning don't become a boxer unless you have trained well. Here's an example in the picture of the boxing, I'll use this term, advisedly, gloves that the Romans used in the early 1st 2nd millennium. These were called sestuses, they're made of leather, and these are the only known ones that have been dug up so far. So you'll notice that the right hand has a larger padding than the left, presumably this man is a right hander and his power punches with his right hand. And by the way, although of course it isn't legal now, there was metal inside this leather. So if he caught you with a right roundhouse, you were indeed going to need rehabilitation. These were found in 2017, they date from the first few hundred years, and both the Naval Academy and West Point continue to box, despite it being now somewhat of a controversial issue. The fact is that it has such a strong tradition that the services have so far resisted the efforts of some people to say we should no longer be boxing. Now one of the things that always reminded sometimes phrase, those who do not read history are condemned to repeat it. And we have had people repeat various names for what we now call CTE over the last hundred and twenty or so years. We know that boxing's been around before ancient Roman times. Boxing was the major source of both our information and the pathology of CTE for a hundred years before our professional sports, but around the late 1890s and up through the 30s, boxing was incredibly popular and to us, it's probably comparable to NFL football because boxers were heroes and certainly the heavyweight champions were well-known, you'll know some of these names when we talk about it briefly, but there was relatively little oversight of boxers. You could box as much as you want as many days a week as you wanted, even multiple fights during the day, but the most interesting thing to me is the fact that both the deficits that these boxers had and the burdens they carried was already known to people in the field and I'll show you that in a minute. The first reports of chronic brain changes was in 1928, but there was an interesting history before 1928 that actually occurred in the United States. So this is the Navy's football team of 1894 and this was the first time that a football helmet was introduced in football because one of the players whose name was Joseph Reeves was told by a Navy doctor that if he got kicked in the head again, he would be risking either death or "instant insanity" and so he made him a leather helmet. Interesting historical point, the helmet also served as the model for the first aviator caps for World War II. You remember seeing those aviator caps that have the ear flaps that would come down making these pilots look very dashing. And there is Cadet Reeves wearing the only one on his team, I noticed, wearing his leather helmet and of course you know that we've had a great deal of controversy about helmets in modern football. The technology has been improving gradually but the human head in all likelihood cannot be protected from athletics which are played by 240 pound people who can run a 4,4,40. Energy equals mass times acceleration, these fellows all weight 140 to 170 pounds and they almost surely were not as fast as our well-trained athletes today. Another little bit of history, Cadet Reeves there, eventually rose to become commander of the U.S. fleet in 1936, this is him over here when the Navy had hats that I guess demanded respect. He was also known as the father of carrier aviation because he was one of the people who believed that we should have planes that could fly off the deck of ships and anyone who knows their naval history knows that initially a number of ships were basically brought back into port and a flat landing surface was built above the ship itself that you could take off with. Those were all by planes by the way. He was head coach of the naval midshipman after he graduated, went to 30 years of training then called back for World War II, he won the Navy cross the Legion of Merit, this man was a hero and he was probably both smart, I have to do all these things because he preserved his brain in the course of playing football. Now, there was a turn of the century, that was in 1894, it was a crisis at the turn of the century which I did not know about until I went into this because the Chicago Tribune was one who referred to football as a death harvest, it was dangerous and violent in that time, in 1905, 18 people died playing football, more than 150 were injured seriously and over five years, average of nine per year, at least 45 football players died during the ballgame of football. In the post in 1905, nearly every death may be traced to unnecessary roughness, picked up unconscious from beneath a mass of other players, it was generally found that the victim would have been kicking the head or the stomach causing internal injuries or concussion which sooner or later ended life. So how did we get from there to something that forced a change? Here's a cartoon from the editorial cartoon from the Cincinnati Tribune, there, I don't know if you can see my pointer but there is sitting on top of the goalposts is death and down below are all of these stricken or dead players and some being carried off the field. So what happened? Well the president in 1905 after the very large number of deaths that year called a summit in Washington, he called the Harvard Yale Princeton athletic directors and the coaches to discuss how to reduce the element of brutality in play and from that summit, they created an organization, the intercollegiate athletic association of the United States and then five years later it became the NCAA. So there's our origin of the NCAA. It was a football fan, this is Theodore Roosevelt, you know he was a very sports and exercise fan believe that this helped make people stronger and better citizens and so forth. So why did he get in at that time? Why couldn't they have handled at the college level? Well there was concern that he would have to outlaw football because of course nobody wants to change the rules once they know how to play the game but perhaps also a personal reason. His son Theodore Roosevelt Jr. got a nasty cut playing football for Harvard and evidently led out a good deal and this is remembered during the year that so many people were killed. And this is a Harvard team who played football, the T. Roosevelt Jr. the star, I don't know exactly where he is in this picture but I think that may be him. That's him up there, good looking guy but perhaps not too good looking after he got the nasty cut but four days after he was hit is when Roosevelt called the coaches of the various Ivy League schools and said get in here and let's figure out how to make it safer. So this meeting transformed football from a sport that the Harvard president called more brutalizing than prize fighting, cock fighting or bull fighting into one more closely representing today's game where now forward passing is allowed and a lot more punts instead of trying to brute force get a first down. This by the way is Roosevelt's son Teddy Jr. in France on July 12th so six days after landing he was on Utah Beach at the day won the Congressional Medal of Honor and several hours after this was taken he was rewarded posthumously because he had an M.I. and died in France but it was another side of the fact that playing football was something that very smart, very capable people did in those days and there was also an interest in making sure that you know these fine young players did not get hurt any more than they had to. Now the early history of what we call CTE at this time is also extraordinarily interesting. In 1906 in JAMA the comment was perhaps the most serious feature of these accidents is a number of concussions in the brain reported no one is ready to say whether the concussion may or may not have serious consequences in after life now I think that means life after football as opposed to in the afterlife but we'll never be able to query the authorized to his intention and in 1906 Nichols and Smith reported in the Boston Medical and Surgeon Journal which became the New England Journal of Medicine that our own experience with the after effects of the cases is not sufficient for us to draw any definite conclusions but from conversations with various neurologists we've obtained very various opinions in regard to the possibility of serious after effects. Keep that in mind the neurologists aren't necessarily heroes in the early days of this and you'll see why. So in 1928 was the first report of the pathology and it was made by Henry Markland who is and this is where we really start the history of the disease. This was in reference to boxers as you might figure out and H.L. Parker in the Journal of Neurology Neuropsychopathology called punch drum traumatic encephalopathy of professional pugilist in the naval medical bulletin in 37 a couple of years later designated a dementia pugilistica because of course if we can put a latin name on something it will sound much more distinguished but basically it means dementia due to boxing and Bowman and Blau laid it out and called it chronic traumatic encephalopathy for people who have chronic problems after head injury and in this particular case they included children in this who presumably had sequelae of brain injuries although not necessarily repetitive. And then McDonald Critchley who was a very well-known, well-respected British neurologist published another article with a single with the same issue calling it chronic traumatic encephalopathy. Over 80 years ago and the title was punch drum syndromes the chronic traumatic encephalopathy of boxers. It was a very valuable one as are a couple of other papers that he had written and showed that the nomenclature was already pretty settled although by the time we got into the 1940s and 50s we had forgotten some of the valuable information that was contained in these older publications by very observant physicians because they did not have the kinds of instrumentation that we have today. Punch drunk is what Corvall called it in 1962. Boxers encephalopathy in '63, Critchley, this is one that you should read if you want to read a few of the important historical pieces, medical aspects of boxing particularly from the neurological standpoint in '57 and then after effects CTE in '66 and then in '69 London boxers were examined and because London was a place where a lot of boxing took place and it was very little oversight. And then Barry Jordan in New York wrote about the clinical spectrum of sports related injury and called it chronic traumatic brain injury '97. In 2005 we published the first case of traumatic encephalopathy in an NFL player after he passed away but up until that time there were not any reported cases of this kind of pathological change in football players only in boxers. So the first evidence of this though, keep in mind what I said about the neurologist was in Markland's 1928 JAMA paper. This is a picture of Markland that I think it was New York City Hospital doing an autopsy in teaching and showing areas of the brain that got injured and he was somebody, oh yes there was New York City Hospital which was named Markland City Hospital for him because he was after 3,000 autopsies, a real expert not only in pathology but also in brain injury due to boxing. This was New York City Hospital which was subsequently labeled Markland Community Hospital City Hospital. I'm not sure if it's still there but everything old is new again, showing you those data from the old days. So here's Markland in the days when I guess you had the smoke to be a real doctor. One sporting writer, this is a quote from him which was the old term for a sports writer. Of note has recently stated that Punch drunk was greatly exaggerated and that he had consulted eminent neurologists who assured him that such a condition did not exist. His comment back was, "I found the opinion of shrewd laymen, many of whom are making a living by observing the physical fitness actions and characteristics of the professional fighter is perhaps more substantial than the opinion of medical experts. A drill and sarcastic comment but on target since neurologists who said a condition as that did not exist were obviously wrong." So this is a picture of the original page of the article in JAMA and the quote is the nomenclature here is just an absolute reminder of how we were not terribly medical back in the old days. Fighters in the early symptoms in whom early symptoms were recognized were said by the fans to be cuckoo, goofy, cutting paper dolls or slug nutty, cutting paper dolls I'm assuming refers to people who had significant cognitive impairment and weren't long-term care facilities but Markland was pretty direct. This was also a table, labor constructed by one of his colleagues who was a promoter and what you can see is the here's the initials of all the fighters and here's their present condition and this is a list which some of you may know because New York was the boxing center of the universe in the thirties and forties. Jack Leonard, most of tender Dundee, Jim Tunney, Jack Jeffery's Fitzsimmons, these were all heavyweight champions and fearsome fighters. So what this implies is that they probably got hit in the head a lot and if you look at their current conditions, this one is Parkinsonian, this one talks slowly and has a gate disturbance, these were punch drunk, these were severe enough to be hospitalized, things slow, talks slow, drags his leg probably another Parkinsonian and then a host of ones who were just regarded as punch drunk. Now comes the pathology, the first that he showed and what he believed was that normally the penetrating arteries that have a perivascular spaces around the artery itself become when you are slammed, choked with blood and interferes with the hemorrhages interferes with the vessels and lead to at least interference with neurological transmission but certainly also probably complete disruption of neurological findings, sorry, neurological care and this is the brain in his case and one of the characteristics and things you see is either a septum-pilucidum that has a cadum that has a space in the middle of it where it is split because of the major traumas and sometimes disappears entirely plus a variety of small hemorrhages in the brain as far as his original case so it is not all that clear but it is clearly a damaged brain in a boxer and this is his hypothesis about how those microhemages all over the place appeared. So if the cause and the pathology of dementia pugilistica was known in the early 20th century and settled by the 90s, all those papers from the British who did pathology on the boxers and the cases weren't terribly common because not everybody boxed, what happened, why what caused such an uptick in the interest of in this particular uncommon disorder? There are two answers, the first was the Middle Eastern Wars, better armor, more rapid evacuation of the injured, frequent IED use which resulted in a blast injury which also usually included a deceleration injury and because of better armor and more rapid evacuation, many people who would have died on the battlefield were successfully removed to where they could be cared for and of course from the standpoint of blast, either a concussion or either a concussive blast or a blast injury itself, a lot of people came to attention with this kind of traumatic abnormality. The second reason was sports and the discovery that American football also produced dementia pugilistica which is the term CTE returned to use that is it moved from dementia pugilistica to chronic traumatic encephalopathy because dementia footballistica was not regarded as something very handy and then of course with looking at other sports players wrestling, rugby, ice hockey, boxing and now although I don't have it in here the first woman who was an MMA fighter I believe who was found to have CTE at post. So football and war were the reasons that everything became more common. The football, the war part was clear to everyone, the football part started with Mike Webster who was a center for the Steelers in the 1970s during their glory days of, sorry 1980s during their glory days and was put in the Hall of Fame in 1997. He never missed ball games. He played for the Steelers for 16 years and then he didn't want to quit although the Steelers wanted him to. So he played for a year with the Kansas City Chiefs and then was forced to retire. But 150 straight games in the pros without injury got him the name Iron Mike and could have been Iron Head Mike. But for years prior to his death he stayed in Pittsburgh and he was known to have had depression, neuropsychiatric syndromes, memory loss and in fact he lived in his truck for a while. He wouldn't let his colleagues help him, his people who played with him and he used to tease himself to get to sleep because his sleep was so disrupted. He died at 50 in September of 2022 and then the brain went to Ben and O'Malley who was a medical examiner in Pittsburgh had just come actually to Pittsburgh from London. He brought the brain over to us at Pitt because they did not in the corners often have any of the stains or ability to examine a brain other than to do hematoxel, but he's sustaining for cells and sliced the brain up. So we sent it in to the Alzheimer's Center Lab where it came back with a picture that I'll show you in a minute which is the characteristic pathological change of CTE. And because it was the only pathology in the books that showed this pattern was called the Metropagealistic Bennett wanted to rename it. And this is a case where he decided that chronic traumatic encephalopathy made the most sense but he did not know that it had been called that several times in the past. So we've now re-emphasized the fact that CTE is the name that it has. There was a lot of controversy over the early findings. If you look out this paper in 2005, you'll find a protesting commentary in that same journal from members of the NFL's Physicians Committee and it was actually longer than our paper basically denying that this was related to his head trauma and this led to a lot of discussion of course between the NFL and college overseers and worried parents about how much damage you can do to your head. But with increasing recognition of the relationship between TBI and neurodegeneration which is what CTE is, the Department of Defense and the Alzheimer's Association of the United States wanted to find ways both to minimize brain injury for obvious reasons for defense and to prevent long-term disease which was the issue for the Alzheimer's Association. Thank you again for joining us. You can learn more about RUSC at NYULangone.org/RUSC. Also be sure to follow this podcast on Twitter @RUSCpodcast.
